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1. A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome

Author

Aung, Tin, Ozaki, Mineo, Mizoguchi, Takanori, Allingham, R Rand, Li, Zheng, Haripriya, Aravind, Nakano, Satoko, Uebe, Steffen, Harder, Jeffrey M, Chan, Anita SY, Lee, Mei Chin, Burdon, Kathryn P, Astakhov, Yury S, Abu-Amero, Khaled K, Zenteno, Juan C, Nilgün, Yildirim, Zarnowski, Tomasz, Pakravan, Mohammad, Safieh, Leen Abu, Jia, Liyun, Wang, Ya Xing, Williams, Susan, Paoli, Daniela, Schlottmann, Patricio G, Huang, Lulin, Sim, Kar Seng, Foo, Jia Nee, Nakano, Masakazu, Ikeda, Yoko, Kumar, Rajesh S, Ueno, Morio, Manabe, Shin-ichi, Hayashi, Ken, Kazama, Shigeyasu, Ideta, Ryuichi, Mori, Yosai, Miyata, Kazunori, Sugiyama, Kazuhisa, Higashide, Tomomi, Chihara, Etsuo, Inoue, Kenji, Ishiko, Satoshi, Yoshida, Akitoshi, Yanagi, Masahide, Kiuchi, Yoshiaki, Aihara, Makoto, Ohashi, Tsutomu, Sakurai, Toshiya, Sugimoto, Takako, Chuman, Hideki, Matsuda, Fumihiko, Yamashiro, Kenji, Gotoh, Norimoto, Miyake, Masahiro, Astakhov, Sergei Y, Osman, Essam A, Al-Obeidan, Saleh A, Owaidhah, Ohoud, Al-Jasim, Leyla, Shahwan, Sami Al, Fogarty, Rhys A, Leo, Paul, Yetkin, Yaz, Oğuz, Çilingir, Kanavi, Mozhgan Rezaei, Beni, Afsaneh Naderi, Yazdani, Shahin, Akopov, Evgeny L, Toh, Kai-Yee, Howell, Gareth R, Orr, Andrew C, Goh, Yufen, Meah, Wee Yang, Peh, Su Qin, Kosior-Jarecka, Ewa, Lukasik, Urszula, Krumbiegel, Mandy, Vithana, Eranga N, Wong, Tien Yin, Liu, Yutao, Koch, Allison E Ashley, Challa, Pratap, Rautenbach, Robyn M, Mackey, David A, Hewitt, Alex W, Mitchell, Paul, Wang, Jie Jin, Ziskind, Ari, Carmichael, Trevor, Ramakrishnan, Rangappa, Narendran, Kalpana, Venkatesh, Rangaraj, Vijayan, Saravanan, Zhao, Peiquan, Chen, Xueyi, Guadarrama-Vallejo, Dalia, Cheng, Ching Yu, Perera, Shamira A, Husain, Rahat, and Ho, Su-Ling

Subjects
Biological Sciences, Genetics, Rare Diseases, Human Genome, Prevention, 2.1 Biological and endogenous factors, Aetiology, Animals, Asian People, Calcium Channels, Case-Control Studies, Chromosome Mapping, Exfoliation Syndrome, Genetic Predisposition to Disease, Genome-Wide Association Study, Glaucoma, Open-Angle, HEK293 Cells, HeLa Cells, Humans, Japan, MCF-7 Cells, Mice, Mice, Inbred C57BL, Polymorphism, Single Nucleotide, Tumor Cells, Cultured, Blue Mountains Eye Study GWAS Team, Wellcome Trust Case Control Consortium 2, Hela Cells, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10(-11)). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: OR(A allele) = 9.87, P = 2.13 × 10(-217); non-Japanese: OR(A allele) = 0.49, P = 2.35 × 10(-31)). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease.

Published
2015

2. A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome

Author

Aung, Tin, Ozaki, Mineo, Mizoguchi, Takanori, Allingham, R Rand, Li, Zheng, Haripriya, Aravind, Nakano, Satoko, Uebe, Steffen, Harder, Jeffrey M, Chan, Anita S Y, Lee, Mei Chin, Burdon, Kathryn P, Astakhov, Yury S, Abu-Amero, Khaled K, Zenteno, Juan C, Nilgün, Yildirim, Zarnowski, Tomasz, Pakravan, Mohammad, Safieh, Leen Abu, Jia, Liyun, Wang, Ya Xing, Williams, Susan, Paoli, Daniela, Schlottmann, Patricio G, Huang, Lulin, Sim, Kar Seng, Foo, Jia Nee, Nakano, Masakazu, Ikeda, Yoko, Kumar, Rajesh S, Ueno, Morio, Manabe, Shin-ichi, Hayashi, Ken, Kazama, Shigeyasu, Ideta, Ryuichi, Mori, Yosai, Miyata, Kazunori, Sugiyama, Kazuhisa, Higashide, Tomomi, Chihara, Etsuo, Inoue, Kenji, Ishiko, Satoshi, Yoshida, Akitoshi, Yanagi, Masahide, Kiuchi, Yoshiaki, Aihara, Makoto, Ohashi, Tsutomu, Sakurai, Toshiya, Sugimoto, Takako, Chuman, Hideki, Matsuda, Fumihiko, Yamashiro, Kenji, Gotoh, Norimoto, Miyake, Masahiro, Astakhov, Sergei Y, Osman, Essam A, Al-Obeidan, Saleh A, Owaidhah, Ohoud, Al-Jasim, Leyla, Al Shahwan, Sami, Fogarty, Rhys A, Leo, Paul, Yetkin, Yaz, Oguz, Çilingir, Kanavi, Mozhgan Rezaei, Beni, Afsaneh Nederi, Yazdani, Shahin, Akopov, Evgeny L, Toh, Kai-Yee, Howell, Gareth R, Orr, Andrew C, Goh, Yufen, Meah, Wee Yang, Peh, Su Qin, Kosior-Jarecka, Ewa, Lukasik, Urszula, Krumbiegel, Mandy, Vithana, Eranga N, Wong, Tien Yin, Liu, Yutao, Koch, Allison E Ashley, Challa, Pratap, Rautenbach, Robyn M, Mackey, David A, Hewitt, Alex W, Mitchell, Paul, Wang, Jie Jin, Ziskind, Ari, Carmichael, Trevor, Ramakrishnan, Rangappa, Narendran, Kalpana, Venkatesh, Rangaraj, Vijayan, Saravanan, Zhao, Peiquan, Chen, Xueyi, Guadarrama-Vallejo, Dalia, Cheng, Ching Yu, Perera, Shamira A, Husain, Rahat, Ho, Su-Ling, Welge-Luessen, Ulrich-Christoph, Mardin, Christian, Schloetzer-Schrehardt, Ursula, Hillmer, Axel M, Herms, Stefan, Moebus, Susanne, Nöthen, Markus M, Weisschuh, Nicole, Shetty, Rohit, Ghosh, Arkasubhra, Teo, Yik Ying, Brown, Matthew A, Lischinsky, Ignacio, Crowston, Jonathan G, Coote, Michael, Zhao, Bowen, Sang, Jinghong, Zhang, Nihong, You, Qisheng, Vysochinskaya, Vera, Founti, Panayiota, Chatzikyriakidou, Anthoula, Lambropoulos, Alexandros, Anastasopoulos, Eleftherios, Coleman, Anne L, Wilson, M Roy, Rhee, Douglas J, Kang, Jae Hee, May-Bolchakova, Inna, Heegaard, Steffen, Mori, Kazuhiko, Alward, Wallace L M, Jonas, Jost B, Xu, Liang, Liebmann, Jeffrey M, Chowbay, Balram, Schaeffeler, Elke, Schwab, Matthias, Lerner, Fabian, Wang, Ningli, Yang, Zhenglin, Frezzotti, Paolo, Kinoshita, Shigeru, Fingert, John H, Inatani, Masaru, Tashiro, Kei, Reis, André, Edward, Deepak P, Pasquale, Louis R, Kubota, Toshiaki, Wiggs, Janey L, Pasutto, Francesca, Topouzis, Fotis, Dubina, Michael, Craig, Jamie E, Yoshimura, Nagahisa, Sundaresan, Periasamy, John, Simon W M, Ritch, Robert, Hauser, Michael A, Khor, Chiea-Chuen, Rochtchina, Elena, Viswanathan, Ananth C, Wong, Tien Y, Xie, Jing, Sim, Xueling, Inouye, Michael, Holliday, Elizabeth G, Attia, John, Scott, Rodney J, Baird, Paul N, Donnelly, Peter, Barroso, Ines, Blackwell, Jenefer M, Bramon, Elvira, Casas, Juan P, Corvin, Aiden, Deloukas, Panos, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin N A, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Wood, Nicholas W, Spencer, Chris C A, Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Pirinen, Matti, Pearson, Richard, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Hunt, Sarah E, Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J, Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T, Liddle, Jennifer, Potter, Simon C, Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, Paul, Widaa, Sara, and Whittaker, Pamela

Subjects
Asian Continental Ancestry Group, Pseudoexfoliation syndrome, Medizin, Locus (genetics), Genome-wide association study, Biology, Inbred C57BL, Exfoliation Syndrome, Polymorphism, Single Nucleotide, Article, Mice, Animals, Calcium Channels, Case-Control Studies, Chromosome Mapping, Genetic Predisposition to Disease, Genome-Wide Association Study, Glaucoma, Open-Angle, HEK293 Cells, HeLa Cells, Humans, Japan, MCF-7 Cells, Mice, Inbred C57BL, Tumor Cells, Cultured, Genetics, Asian People, medicine, SNP, Allele, Polymorphism, Cultured, Case-control study, Glaucoma, Odds ratio, Single Nucleotide, medicine.disease, eye diseases, Tumor Cells, Open-Angle, Etiology
Abstract

Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10(-11)). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: OR(A allele) = 9.87, P = 2.13 × 10(-217); non-Japanese: OR(A allele) = 0.49, P = 2.35 × 10(-31)). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease.

Published
2014

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